A great deal has been learned about the molecular basis of innate recognition of microbial pathogens in the last decade. It is generally accepted that many somatic cells express a range of pattern recognition receptors that detect potential pathogens independently of the adaptive immune system (see Janeway et al., Annu Rev. Immunol., 20:197 (2002)). These receptors are believed to interact with microbial components termed pathogen associated molecular patterns (PAMPs). Examples of PAMPs include peptidoglycans, lipotechoic acids from gram-positive cell walls, the sugar mannose (which is common in microbial carbohydrates but rare in humans), bacterial DNA, double-stranded RNA from viruses, and glucans from fungal cell walls. PAMPs generally meet certain criteria that include, (a) their expression by microbes but not their mammalian hosts, (b) conservation of structure across the wide range of pathogens, and (c) the capacity to stimulate innate immunity. Toll-like Receptors (TLRs) have been found to play a central role in the detection of PAMPs and in the early response to microbial infections (see Underhill et al., Curr. Opin. Immunol., 14:103 (2002)). Ten mammalian TLRs and a number of their agonists have been identified. For example, TLR7 and TLR9 recognize and respond to imiquimod and immunostimulatory CpG oligonucleotides (ISS-ODN), respectively. The synthetic immunomodulator R-848 (resiquimod) activates both TLR7 and TLR8. While TLR stimulation initiates a common signaling cascade (involving the adaptor protein MyD88, the transcription factor NF-kB, and pro-inflammatory and effector cytokines), certain cell types tend to produce certain TLRs. For example, TLR7 and TLR9 are found predominantly on the internal faces of endosomes in dendritic cells (DCs) and B lymphocytes (in humans; mouse macrophages express TLR7 and TLR9). TLR8, on the other hand, is found in human blood monocytes (see Hornung et al., J. Immunol., 168:4531 (2002)).
Interferons (INFs) are also involved in the efficient induction of an immune response, especially after viral infection (Brassard et al., J. Leukoc. Biol., 71:568 (2002)). However, many viruses produce a variety of proteins that block interferon production or action at various levels. Antagonism of interferon is believed to be part of a general strategy to evade innate, as well as adaptive immunity (see Levy et al., Cytokine Growth Factor Rev., 12:143 (2001)). While TLR agonists may be sufficiently active for some methods of treatment, in some instances the microbial interferon antagonists could mitigate the adjuvant effects of synthetic TLR agonist.
A more specific response to microbial infections is based on active or passive immunization. If universal immunization is not considered cost-effective (or pharmacoeconomically viable), identification of a population at-risk that would benefit from immunoprophylaxis may be cost-effective, although identifying that population may be not straightforward. Nevertheless, there are some clearly defined at-risk populations for certain bacterial infections, such as staphylococcal infections, including dialysis patients, patients with ventriculoperitoneal shunts, patients at-risk of infective endocarditis, and residents of nursing homes, all of which suffer from chronic conditions that place them at a prolonged increased risk from staphylococcal infections. Many of these patients are also at increased risk for acquiring healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA). Blocking colonization of Staphylococcus, however, may be more achievable than protecting against infection.
Passive immunoprophylaxis using either polyclonal antibodies (Capparelli et al., Antimicrob. Agents Chemo., 49:4121 (2005)) or monoclonal antibodies (mAbs) (www.biosynexus.com/productcandidates.html) may provide immediate (although short-term) protection for patients who either cannot wait for a vaccine effect to occur or whose immune systems are too compromised to mount a response to a vaccine. One potential indication for passive immunoprophylaxis is a hospital outbreak of MRSA-related infections. In such cases, exposed individuals may benefit from immediate prophylaxis, whereas individuals residing on the same ward or chronic care facility may benefit from active immunization. Moreover, intensive care unit patients are potential beneficiaries of passive immunoprophylaxis, as each of them would likely acquire one or more risk factors for staphylococcal infections.